Abstracts

Progestins modulate seizures of women and in rodents. The progesterone (P) metabolite, 5[alpha]-pregnan-3[alpha]-ol-20-one (3[alpha],5[alpha]-THP) has anti-seizure effects. 3[alpha],5[alpha]-THP can also dampen activity of the hypothalamic-pituitary-adrenal (HPA) axis; and stress can affect seizure incidence. The current studies examined whether progestins[apos] modulation of seizures is due in part to effects on HPA function. In Experiment 1, effects of P to mediate seizures of sham or adrenalectomized (ADX) rats were examined. Ovariectomized, ADX or sham ADX rats were administered P (4 mg/kg, SC) three hours prior to pentylenetetrazole (PTZ; 70 mg/kg, IP). Experiment 2 examined whether replacement of corticosterone, which is a primary product of the adrenals, could reinstate P[apos]s anti-seizure effects in ADX rats. ADX rats had access to corticosterone (25 mg/ml) or vehicle in their drinking water for 4 days prior to administration of P or vehicle as above. In Experiment 1, P significantly reduced the number of tonic seizures of sham, but not ADX rats, compared to vehicle administration. In Experiment 2, The number of PTZ-induced seizures was modestly reduced by P, compared to vehicle administration, in corticosterone-replaced rats. Plasma corticosterone levels were increased in sham ADX rats administered vehicle; whereas P-administered rats had basal levels of corticosterone, irrespective of ADX condition. Levels of 3[alpha],5[alpha]-THP in the hippocampus were higher in P-, but not vehicle-administered, rats irrespective of ADX condition. Together, these data suggest that progestins[apos] modulation of seizure activity may involve effects on the HPA axis, albeit perhaps not entirely through direct actions of corticosterone. Ongoing studies are investigating other possible HPA factors that may underlie some of progestins[apos] anti-seizure effects. (Supported by The National Science Foundation (IBN03-16083), The National Institute of Mental Health (MH06769801), and The Epilepsy Foundation.)